Anatoly Derevianko,
Director, Institute of Archeology and Ethnography of the Russian Academy of
Sciences

HOST

Steve
Usdin, Senior Editor

SEGMENT 1

STEVE
USDIN: I'm Steve Usdin. Paleogenomics has made it possible to sequence the
genomes of Neanderthals. A paleogenomics pioneer joins us to discuss what it
means to be human. I'm Steve Usdin. Welcome to BioCentury This Week.

NARRATOR:
Connecting patients, scientists, innovators, and policymakers to the future of
medicine. BioCentury This Week.

STEVE
USDIN: Svante Pääbo, a Swedish scientist, has developed techniques for
extracting and analyzing ancient DNA. Pääbo led a team that sequenced the
genome of modern human's closest relatives, the Neanderthal. To the
astonishment of many paleontologists, Pääbo's research shows that Neanderthals
mated with modern humans, and echoes of those encounters live on in the DNA of
many people who are alive today.

Just
as scientists began to study what physical or behavioral traits we've inherited
from Neanderthals, Pääbo's team announced another discovery that changes
conceptions of human evolution. They determined that ancient DNA from a tiny
bone fragment discovered in a cave in a remote region of Russia came from a new
human species. This species, Denisovans, also interbred with modern humans. And
like Neanderthals, Denisovans live on today in the DNA of people who live in
Papua New Guinea and in the genomes of Australian Aborigines. Beyond rewriting
the story of human origins, Pääbo's team and other paleogenomics researchers
are studying Neanderthal and Denisovan genomes for insights into what makes
humans different from other primates.

To
discuss his work sequencing DNA from Neanderthals and other early humans, and
how it changes our understanding of what it means to be human, I'm pleased to
be joined by Dr. Svante Pääbo. Dr. Pääbo, your team spent a great deal of
effort in sequencing Neanderthals. And there was a lot of technical work that
was involved in that. But I want to talk to you today about kind of what it
means and what we've learned from it. To start with, what did we learn about
human origins from sequencing the Neanderthal genome?

SVANTE
PÄÄBO: Well, so we learned that modern humans do come out of Africa, but first
of all in Africa, come out of Africa. And then we meet, somewhere around
40,000, 50,000 years ago, we meet other forms of humans, for example,
Neanderthals in Europe and western Asia, and other forms in Asia. And we don't
just replace them. We mix with them. So as a result, if you're ancestry today
comes from Europe or Asia, somewhere between 1% or 2% of your DNA actually
comes from Neanderthals.

STEVE
USDIN: So that's really fascinating. And about the origin story, so before your
work, there was kind of a debate about origins, about whether humans came out
of Africa originally or whether they developed separately in different places,
right? And you've kind of definitively shown that we all came out of Africa,
but it's a complicated story. It's in two waves, right?

SVANTE
PÄÄBO: Yes. So Neanderthals also, of course, have an origin. And the most
likely place of that origin is in Africa. So somewhere half a million years ago
or so the ancestors of Neanderthals come out of Africa and in Europe and
western Asia evolve into what we call Neanderthals today. And they actually
have relatives in Asia that evolved to other forms there.

And
then modern humans, somewhere between 100,000 and 200,000 years ago evolve
inside Africa. And somewhere around 100,000 years ago, we find the first
fossils of modern humans in the Middle East. But they really start spreading
seriously out of that area only around 50,000, 60,000 years ago.

STEVE
USDIN: And during that period when they were together, humans and Neanderthals
then, they mixed. The other thing that you found, which is really incredible,
is you found a whole new species of early humans. Can you tell us how did you
find them? And what do we know about them?

SVANTE
PÄÄBO: Yes. So we worked together with Russian archaeologist in Novosibirsk,
Anatoly Derevianko and his team. And in 2008, they excavated in a cave on the
border between Russia and Mongolia in southern Siberia and found a tiny little
bone, a fragment of the last phalanx of a pinkie of a child. They were actually
very skilled in realizing that this might be a bone from a human.

And
we got this fragment of this bone and were convinced that it would be either a
modern human or a Neanderthal and were extremely surprised when we started
sequencing the DNA and found that it was related to Neanderthals, but very far
back, at least 200,000 years ago or so. So Neanderthals and this other form of
humans had a long, independent history from each other. So we thought a lot
about what we would call this new form of humans, and settled on Denisovans,
after Denisova Cave, the place they were first found. Just as Neanderthals are
named after Neandertal.

STEVE
USDIN: So the really kind of interesting thing also, to follow the story
forward, is that not only did you find this new form of human simply from this
little tiny bit of a pinkie, but then you also later found that there are
people who are alive on earth today who have incorporated the DNA or have the
DNA from this Denisovan people, right?

SVANTE
PÄÄBO: Yes. So when we then sequenced their genome, we could ask the same
questions as we had done with the Neanderthal genome. Have these Denisovans
contributed to any people that live today? And to our surprise, we found a
contribution, but not in central Asia or Siberia, but mainly in the Pacific, so
in Papua New Guinea, Aboriginal Australians, Fiji, and so on.

STEVE
USDIN: And the other thing also -- I'm sorry -- to get back to the Neanderthals
that's really interesting is that most people who are in Europe and in Asia
have got a little bit of traces of Neanderthal DNA in them. But since humans
came out of Africa, people from Africa don't have that DNA, right?

SVANTE
PÄÄBO: Yes. So we find no evidence of Neanderthal DNA in Africans. Or the
little, little bit one can detect is actually due to the infill back to Africa
from Europe or western Asia. But that's not to say that there are no
contributions in Africans from any of these earlier forms. There are some
indications from studying variation today that there are some old lineages also
in Africa. So presumably, modern humans evolved somewhere in Africa, spread
across Africa, and probably then mixed with other early forms that existed
there. But we have no genomes of those forms.

STEVE
USDIN: Dr. Pääbo's research has implications beyond human origins. When we
return, what does Neanderthal DNA mean for us?

NARRATOR:
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SEGMENT 2

STEVE
USDIN: We're back with Dr. Svante Pääbo discussing ancient DNA. Dr. Pääbo, I
sent my results off, like a lot of people do, to a personal genomics service.
And it came back and said I'm 2.8% Neanderthal. First, is that accurate? Is my
DNA really 2.8% Neanderthal? And second, what should I think about that.

SVANTE
PÄÄBO: Well, first of all, I think that sounds a little high. And I think most
of these companies in reality actually measure in addition to the Neanderthal
contribution a lot of statistical noise. Some of them come out, for example,
finding Denisovan contribution in Europe, which doesn't make sense.

There
are better methods on the way. There were two papers published in January from
two different research groups. So I think we will be able in the future to tell
much better how much of you is Neanderthal.

STEVE
USDIN: And what's the difference? I mean, what should people think about that,
besides the fact that it's tremendously cool?

SVANTE
PÄÄBO: Well, I think we're beginning to learn that sometimes this can have
consequences, some consequences for how we sort of look or behave, maybe. But
for most of it, I think it's just DNA as any other part of your DNA that you
needn't think have any special consequences at all for you.

STEVE
USDIN: So you've done some research, though, looking at the DNA that's
different, kind of the contribution of Neanderthals to modern humans. And some
of it's focused, surprisingly, on type 2 diabetes. Can you talk about that?

SVANTE
PÄÄBO: Yes. So there's a group in Boston who did a big study in Native American
groups in Mexico and found a new risk allele, a variant of a gene that
transports lipids across the cell membrane. And the risk variant there turns
out to come from Neanderthals into the ancestors of Native Americans,
presumably when those ancestors were in Asia. So that's quite fascinating to
me, because that's sort of an example of something that comes from Neanderthals
and actually has consequences for us today.

STEVE
USDIN: And you're not only looking at ancient DNA. You've also looked at
primate DNA. And you're doing comparisons with humans. Some of your work is
also looking at what might be responsible for creating speech and language. Can
you talk about that and what you've seen? Well, for example, did Neanderthals
speak?

SVANTE
PÄÄBO: So speech and language is obviously a very complex trait. And many, many
genes are involved. But there is one gene that is known to have effects,
because when one copy is damaged in a present-day human, we have a severe and
specific language and speech problem. That gene is called FOXP2. And it's
transcription factors. Its function is to turn on and turn off other genes.

And
the protein it encodes have two changes in amino acids specific to humans. And
they are in no other apes or monkeys. We have actually shown that those two
amino acids are important, because if we engineer them in into a mouse, the
mouse actually peeps differently. It vocalizes differently. And it has
consequences for aspects of motor learning in the mouse.

So
we are very interested to see, in the Neanderthal and Denisovan genomes, if
they share these changes with us or not. And they do, actually. So they looked
like us.

STEVE
USDIN: So can you go back farther and find earlier humans that don't have it?
Can we find out when that evolved?

SVANTE
PÄÄBO: Hopefully in the future. So we are applying our very best new techniques
now to older fossils. And we've just succeeded late last year to retrieve DNA
from a 400,000-year-old probably ancestral Neanderthals or so. But so far we
have very little of the genome, just a tiny little part of mitochondrial
genome. But I think that will happen, yes. We will be able to go further back
within the last half million years or one million years.

STEVE
USDIN: So you think there's a limit, though. At some point, the DNA degrades.
You're not going to be able to go back and get dinosaur DNA or something like
that.

SVANTE
PÄÄBO: Yes. I do think that sort of the furthest back we can go is probably in
the permafrost, where things are constantly frozen since they died. And there's
a group that retrieved from a horse 700,000-year-old DNA. But somewhere there
is a limit. I would say on this side of one million years.

STEVE
USDIN: Well, thank you. Does sequencing extinct beings mean they can be brought
back to life? If that's possible, should it be done? We'll talk about that in a
moment.

SEGMENT 3

NARRATOR:
Now back to BioCentury This Week.

STEVE
USDIN: We're back with Dr. Svante PÄÄBO. Dr. PÄÄBO, George Church, when we had
him on this show, he talked about bringing back carrier pigeons and mammoths
from extinction. Is that possible? And do you think it should be done?

SVANTE
PÄÄBO: I would actually say it's not possible in any real sense. So for
example, the Neanderthal genome now is the best genome we have of anything
extinct. We still, though, have only about 2/3 of the genome, that single copy
that exists only once, where we can map these short little fragments to it.

Then
there is another 1/3 of the genome that's composed of repeated sequences that
occur twice or more times. And there, of course, when you have tiny little
fragments, you don't know from which copy they came. So there's 1/3 of the
genome that contains important things too that we will never know the exact
organization of. And in reality, when we try to engineer in single changes into
stem cells today, we struggle to put in even a few changes correctly. And say,
if we talk about the Neanderthals, we're now talking about engineering in tens
of thousands of changes in those 2/3 of genome we know. So I would actually say
within reasonable time frame that we can overlook, it's impossible.

STEVE
USDIN: So that's a Neanderthal. And what he talked about about the mammoth, for
example, is not really, when you get down to it, bringing an extinct mammoth
back, but trying to tweak the genome of an elephant to make it a bit more like
a mammoth.

SVANTE
PÄÄBO: Yes. I mean, what I do think can happen is that you in the future with
great effort make an elephant that's a bit hairy, a bit different color. But it
will then be an elephant masquerading as a mammoth. It's not a mammoth.

STEVE
USDIN: So I want to switch onto another topic, and getting back to kind of the
social meaning of your work. When you talk about human origins and DNA, really
at some point sooner or later people start talking about race, racial
differences among humans today. What has your work shown about the significance
of racial differences at the level of the genome?

SVANTE
PÄÄBO: Well, that's not only our work. It's actually work of many, many groups
who study genetic variation, for example, the 1000 Genomes Project, which have
sequenced over 1,000 complete genomes from all over the world. And I find it
fascinating that if you look at those data, you really see that there are no
absolute fixed differences I would say between what we call races.

So
the biggest sort of genetic difference between populations I think we have is
between Africans and non-Africans. And if you look in those data over tens of
millions of variable positions, you don't find a single position in the genome
that's a real difference, like my mother would think of a genetic difference,
where everybody in Africa has something, everybody outside Africa has something
else. If we take a less stringent criteria and say 95% in Africa, 5% or less
outside, it's 12 differences. So it's really nothing. So this really means that
from looking at the particular part of our genome only, you cannot with 100%
certainty say if a person comes from Africa or outside Africa.

STEVE
USDIN: So another thing, now kind of jumping around to another topic, you
started your work looking at the DNA from mummies. And one of the things I'm
wondering about there is, have you been able to determine, the people who were
Egyptians at the time of what we think of the classical Egypt of the pyramids
and the pharaohs, were they the same people as there are in Egypt today?

SVANTE
PÄÄBO: That was really a dream I had when I started doing this. And the sad
thing is really that preservation conditions in Egypt are very bad for DNA.
It's really related I think mainly to climate and how one prepared the mummies
that we have not been able to retrieve yet, but it will come, really reliable
DNA sequences from whole genomes at least from Egypt. So I can't really answer
that.

STEVE
USDIN: Well, that'll be a very interesting one. And another one, kind of
jumping around to another thing that I found very interesting in your book, is
that you talked about using genome sequencing to learn some basic things about
evolution. And you give the example of the sloths, of the tree sloths. Can you
tell that story? Yes.

SVANTE
PÄÄBO: So there are cases, many cases in evolution where animals have evolved
to similar lifestyles. So for example, there are two forms of tree sloths in
South America, two-toed and three-toed tree sloths. And there used until 15,000
or 10,000 years ago, to be many forms of sloths that were ground-dwelling, big
sloths. So there were really two ideas about this. Either the two tree sloths
were very closely related to each other and survived until present day due to
some physiology they have in common, or they were not closely related to each
other and simply survived because they were in the trees, so when humans came,
they killed off the ground-dwelling sloths but couldn't get into the trees.

STEVE
USDIN: And that seems to be what -- in short, that's what you found.

SVANTE
PÄÄBO: Yes. And that is what we have found. So this is a case of independently
two animals evolving to the same sort of morphology and way of behaving. Now,
many examples of that sort of parallel evolution, suggesting that selective
forces are very strong and can form how we look quite quickly.

STEVE
USDIN: Dr. Pääbo, one of the things I think that's confusing, I'm wondering if
you could clarify a little bit. A lot of people, when they went to school, they
learned that a species, the definition is a group of animals or people who
can't breed with others, that can only breed with themselves. And obviously,
that's not what happened with humans and Neanderthals.

SVANTE
PÄÄBO: Yes. I think species is a complicated thing, because there's no
definition of a species that applies to all cases of different groups in
nature. So for example, polar bears and brown bears can indeed breed with each
other and have fertile offspring, yet are very, very different. It would be
ridiculous to call them the same species.

So
I think it's actually a very academic thing to discuss what is a species or a
subspecies. If we now describe what happened when Neanderthals and modern
humans met, that one did mix with each other, Neanderthals ended up
contributing about 1% of the DNA to people today, we have described what is
interesting. And others can fight about if we are two different species or not.

STEVE
USDIN: And the other thing that's interesting, so they contributed about 1% or
maybe in some people a little bit more. But there are also parts of the
Neanderthal genome that didn't get incorporated into humans. Can we learn
something from that?

SVANTE
PÄÄBO: Yes. So there are two studies that recently appeared that looked across
the genome of hundreds of humans to see where Neanderthals had contributed and
where we seem to be resistant to it, where one would expect statistically to
see Neanderthal contribution but you don't. And then we asked, in those parts
of the genome where we don't accept Neanderthal contributions, what genes are
particularly located there? And it turned out to be genes that are expressed in
the male lines and testicles.

So
this suggests that the hybrids, Neanderthal-human hybrids, may have had some
problems with fertility in the males. And that's actually quite a common thing,
where closely related species or populations hybridize with each other, say
horses and donkeys, that it's the male offspring that has problems with
fertility, whereas the female offspring generally can have.

STEVE
USDIN: So does that suggest that in the kind of inner-mixing between modern
humans and Neanderthals, that most of what's come to us would have been from
the maternal side?

SVANTE
PÄÄBO: Yes. So it suggests that it would be the female offspring that then went
on, had children on their own, and contributed to people today.

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SEGMENT 4

STEVE
USDIN: We're finishing up with Dr. Svante Pääbo. Dr. Pääbo, I want to jump back
to something we talked about earlier. When you said that there are no clear
genetic differences between, for example, Africans and people in Europe, people
who are watching the show might say, well, what does that mean? We can look at
people and we can see racial differences. Are you saying that there's no
underlying genetic causes?

SVANTE
PÄÄBO: So what I'm saying is there are no absolute differences in terms of
everyone has one variant in one region, everyone has another variant elsewhere.
There are differences in frequencies in many, many genes that have
consequences, for example, for skin color, hair texture, facial features. There
is a very accomplished study of just body height, which is a very simple trait
to measure and that is also largely inherited that shows there are hundreds of
genes involved in this. So there's no absolute difference between short people
and long people, but small differences in many, many genes.

STEVE
USDIN: Wow. So another kind of common perception, it's gone into the language
even, people say that something is in my DNA or even companies even say that
something's in their DNA. It suggests a certain level of genetic determinism.
How much of our behavior, of our social traits, really is in our genes?

SVANTE
PÄÄBO: Well, that's of course a billion dollar question that no one can answer
I think just straight off. I do think, though, that almost any trait of
interest we think about is determined both by genetics and by environment. And
I find it sort of sad that we come to a situation where we will stress the DNA
and inheritance so much that we perhaps don't focus on what we can change in
our society.

STEVE
USDIN: So that also kind of -- getting back to the Neanderthal, I think one of
the ways to kind of get at these things is to ask, what is it that made modern
humans prevail and succeed where Neanderthals, and Denisovans, and other kinds
of early humans didn't? Do you think we might actually know the answer to that
some day?

SVANTE
PÄÄBO: I hope we will one day. And we have a tool for it now with the
Neanderthal genome. We can make a catalogue now of all of the absolute
differences where all people today, no matter where we live, have some change
in the genome but the Neanderthals look like apes. And that's a very short list.
It's around 31,000 changes.

So
we can begin to look at these. And biologists can now start making experiments
to find out what those changes do. And some of them may be behind the fact that
in just 50,000 years, we spread all over the world, colonized every part on the
planet. We're flying to Mars now. And we are 7 billion people instead of in the
hundred thousands.

STEVE
USDIN: And what about the difference between the Neanderthals and modern
humans? How many differences are there there?

SVANTE
PÄÄBO: So absolute differences would be in the order of 60,000 or something
like that. But we don't know the variation among Neanderthals yet, so we can
only really say that there are a little over 30,000 differences to Neanderthals
that all humans today have in common.

STEVE
USDIN: And how many of those differences code for a protein, something that we
think actually would have an effect?

SVANTE
PÄÄBO: So in protozoas, 97 changes in 87 different genes.

STEVE
USDIN: And do we know what that means, what the actual functional meaning of
that is?

SVANTE
PÄÄBO: Well, the dirty little secret of genomics is really that we are very,
very bad at looking at single changes we pick out in the genome and saying what
consequences they have. So we just make guesses. There are genes in there, for
example, that does have to do with development of nerve cells in the brain that
may be particularly interesting. There are others that have to do with skin and
skin morphology, for example.

STEVE
USDIN: Well, thanks very much. We could talk all week about this. But that's
all the time we've got today.

I'd
like to thank Svante Pääbo. Remember to share your thoughts about today's show
on Twitter. Join the conversation by using the hashtag #BioCenturyTV. I'm Steve
Usdin. Thanks for watching.